Platelets are cell-like anucleated fragments, found in the blood of all mammals that support primary hemostasis by forming hemostatic plugs at sites of vascular injury. Thrombosis is the pathological condition wherein improper activity of the hemostatic mechanism results in intravascular thrombus formation. Activation of platelets and the resulting platelet aggregation has been associated with a variety of pathophysiological conditions including cardiovascular and cerebrovascular thromboembolic disorders, for example, the thromboembolic disorders associated with unstable angina, myocardial infarction, transient ischemic attack, stroke, thrombotic disorders such as peripheral arterial disease, and diabetes.
Glycoprotein IIb/IIIa receptors (hereinafter referred to as GP IIb/IIIa receptors) are found on the surface of platelets and belong to a superfamily of adhesion receptors known as integrins, which are composed of transmembrane glycoproteins containing α and β subunits. Fibrinogen, fibronectin, vitronectin and von Willebrand factor (vWF) are proteins that bind to and crosslink GP IIb/IIIa receptors on adjacent activated platelets and thereby effect aggregation of platelets.
The binding of fibrinogen is mediated in part by the Arginine-Glycine-Aspartic acid (RGD) recognition sequence which is common to the adhesive proteins that bind GP IIb/IIIa receptors (Ferguson, J. J. and Zaqqa, M., Drugs, 1999, 58, 965-982; Mousa, S. A and Bennett, J. S., Drugs of the future 1996, 21, 1141-1154; Ojima, I., Chakravarty, S. and Dong, Q., Bioorganic and Medicinal Chemistry 1995, 3, 337-360).
Platelets are activated by a number of agonists that include adenosine diphosphate (ADP), thrombin, serotonin, arachidonic acid, collagen and adrenaline among others, which are released in the body as a result of various physiological reactions. Regardless of the nature of the stimuli involved in the activation of platelets, the final step of platelet aggregation is the binding of fibrinogen to the activated GP IIb/IIIa receptors on the surface of platelets thereby cross-linking platelets. (J. Lefkovits, E. F. Plow, E. J. Topol 1995, New England Journal of Medicine, 332, 1553-1559). This makes GP IIb/IIIa receptors ideal targets for inhibiting platelet aggregation. The development of GP IIb/IIIa receptor antagonists would, therefore, provide an effective strategy for the control of platelet aggregation and hence thrombi formation (Bennett, J. S, Annual Reviews of Medicine, 2001, 52, 161-184).
Cardiovascular diseases are among those that cause the highest mortality throughout the world. Thus, in order to prevent the cardiovascular diseases caused by platelet aggregation, there is an increased necessity for efficient anti-platelet aggregating treatment with drugs possessing specific characteristics namely efficacy, negligible side effects and fast onset of action.
Current antiplatelet drugs are effective against only one type of agonist; these include aspirin, which acts against arachidonic acid; ticlopidine, which acts against ADP; and hirudin, which acts against thrombin.
Until recently, aspirin has been widely used as an inhibitor of platelet function (New England Journal of Medicine, 1994, 330, 1287). While the benefits of aspirin have been demonstrated, there are clinical limitations of this drug. These limitations have provided the impetus for the development of newer antithrombotic agents having therapeutic advantages over aspirin.
Ticlopidine, a thienopyridine derivative, has also been effectively used in patients suffering cardiovascular diseases. However, this drug is associated with a number of serious side effects. Recently, a common pathway for all known agonists has been identified, namely the platelet GP IIb/IIIa complex, which is the membrane protein mediating platelet aggregation (Phillips et al. Cell 1991, 65, 359-362). The development of GP IIb/IIIa receptor antagonists represents a promising new approach for antiplatelet therapy.
A fibrinogen receptor antagonist (hereinafter referred to as FRA) is an agent that inhibits the binding of fibrinogen to the platelet bound fibrinogen receptor GP IIb/IIIa and thereby prevents platelet aggregation and thrombus formation. Inhibition of platelet aggregation is a major target for the prevention and treatment of cardiovascular diseases.
Known fibrinogen receptor antagonists are:
1. Monoclonal antibodies—e.g. abciximab
2. Parenteral compounds
                a) Synthetic peptides—e.g. eptifibatide        b) Non peptide peptidomimetics—e.g. tirofiban3. Oral compounds—e.g. roxifiban, gantofiban1. Monoclonal Antibodies:        
In 1985, a mouse monoclonal antibody against GP IIb/IIIa, known as c7E3, was generated. Subsequently, the Fab fragment of a chimeric human-mouse genetic reconstruction of c7E3 (c7E3 Fab), known as abciximab, was used in clinical trials (Drugs of the Future, 1995, 20, 457-463). Abciximab was launched in 1995 on the US market, as an intravenous preparation.
2. Parenteral Compounds:
a) Eptifibatide, a synthetic cyclic peptide (J. Med. Chemistry, 2000, 43, 3453-3473) was designed as a mimic of a snake venom peptide namely barbourin. Eptifibatide is effectively used for the inhibition of platelet aggregation.
b) Based on the observation that peptides containing the tripeptide Arginine-Glycine-Aspartic acid (RGD) sequence function as fibrinogen receptor antagonists, scientists attempted the development of non-peptide peptidomimetics as inhibitors of platelet aggregation (Hartman et. al. J. Med. Chemistry 1992, 35, 4640-4642).
A number of non-peptide fibrinogen receptor antagonists are known and are disclosed in the patents and other publications, which follow:
JP 10-017469 discloses oxyisoindole derivatives possessing fibrinogen receptor antagonistic activity.
EP-A-712844 discloses condensed ring carboxylic acid compounds having platelet GP IIb/IIIa receptor antagonist activity that are useful for the prophylaxis and treatment of thrombotic diseases.
EP-A-540334 discloses isoindolinone compounds as fibrinogen receptor antagonists, which are used in inhibiting the binding of fibrinogen to blood platelets and for inhibiting the aggregation of blood platelets.
WO 96/26187 discloses a series of 3,4-dihydro-1(1H)-isoquinolinone based compounds as fibrinogen receptor antagonists useful for inhibiting platelet aggregation with oral activity. Tirofiban, a non-peptide antagonist, developed by Merck & Co. is the first agent of this class to be used for the treatment of cardiovascular diseases (Hartman G. D. et. al., J. Med. Chemistry, 1992, 35, 4640-4642).
U.S. Pat. No. 5,726,185 describes acetic acid derivatives useful for the treatment or prophylaxis of illnesses which are caused by the binding of adhesive proteins to blood platelets and by blood platelet aggregation and cell-cell adhesion.
U.S. Pat. No. 5,378,712 describes N-acyl-alpha-aminocarboxylic acid derivatives and N-acyl-alpha-amino acid derivatives which are useful for the treatment or control of illnesses which are caused by the binding of adhesive proteins to blood platelets and by blood platelet aggregation and cell-cell adhesion.
WO 93/07867 discloses substituted beta amino acid derivatives as platelet aggregation inhibitors.
3. Oral Compounds:
There are currently no oral preparations on the market. Many compounds that had reached Phase III clinical trials had to be withdrawn due to lack of efficacy or adverse effects such as major bleeding episodes and thrombocytopenia.
EP-A-483667 describes cyclic imino derivatives having aggregation inhibiting effects.
WO 95/18619 describes bicyclic fibrinogen antagonists as inhibitors of platelet aggregation.
WO 95/14683 discloses isoxazolines and isoxazoles that are useful as antagonists of the platelet GP IIb/IIIa fibrinogen receptor complex for the inhibition of platelet aggregation, as thrombolytics and/or for the treatment of thromboembolic disorders.
Gantofiban is a platelet GP IIb/IIIa antagonist for the treatment of various thrombotic diseases, such as acute coronary syndromes (J. Gante et al. Bioorganic and Medicinal Chemistry letters, 1996, 6:20, 2425-2430); Cromafiban is an orally active GP IIb/IIIa antagonist, which was being developed by COR Therapeutics as a potential treatment for thromboembolic disorders, acute coronary syndromes and stroke (Scarborough R. M., et. al, J. Med. Chemistry, 2000, 43:19, 3453-3473).
Even though several FRAs are described in the prior art, there is still a need to develop specific agents having fibrinogen receptor antagonistic activity in the advent of the increased mortality rate among patients suffering from cardiovascular diseases.
The FRAs currently available are all intravenous preparations, limiting their use to a hospital environment. A clear clinical need and market exists for FRAs that can be administered by more patient-compliant routes.
A focussed research on FRAs by the present inventors has resulted in the discovery of novel compounds. These compounds are effective inhibitors of GP IIb/IIIa receptors. Moreover, the compounds of the invention inhibit GP IIb/IIIa receptors with an efficacy comparable to the known FRAs, which are under clinical trials. Therefore, the compounds of the present invention are candidate agents for the treatment of thrombotic diseases.